Akeega

/ J-C Health Care Ltd., Israel

Before initiation of the drug therapy, positive BRCA status must be established using a validated test method .
The recommended starting dose is 200 mg/1000 mg (two 100 mg niraparib/500 mg abiraterone acetate tablets), as a single daily dose at approximately the same time every day. The 50 mg/500 mg tablet is available for dose reduction.
Medical castration with a gonadotropin-releasing hormone (GnRH) analogue should be continued during treatment in patients not surgically castrated.
Dosage of prednisone or prednisolone
the drug is used with 10 mg prednisone or prednisolone daily.
Duration of treatment
Patients should be treated until disease progression or unacceptable toxicity.
Missed dose
If a dose of either the drug, prednisone or prednisolone is missed, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. Extra tablets must not be taken to make up for the missed dose.
Method of administration
The tablets must be taken as a single dose, once daily. Should be taken on an empty stomach, at least 1 hour before or 2 hours after a meal. For optimal absorption, tablets must be swallowed whole with water, they must not be broken, crushed, or chewed.
Precaution to be taken before manipulating or administering the product
Women who are or may become pregnant should wear gloves when handling the tablets.
See prescribing information for full details.

Indicated with prednisone or prednisolone for the treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA 1/2 mutations (germline and/or somatic) in whom chemotherapy is not clinically indicated.

* Hypersensitivity to the active substances or to any of the excipients.
* Women who are or may become pregnant.
* Severe hepatic impairment [Child-Pugh Class C].
* Treament with this medical product and prednisone or prednisolone is contraindicated in combination with Ra-223 treatment.

Haematological adverse reactions
Haematological adverse reactions (thrombocytopenia, anaemia and neutropenia) have been reported in patients treated with the drug.
Testing complete blood counts weekly for the first month, every two weeks for the next two months, followed by monthly monitoring for the first year and then every other month for the remainder of treatment is recommended to monitor for clinically significant changes in any haematological parameter while on treatment.
Based on individual laboratory values, weekly monitoring for the second month may be warranted.
If a patient develops severe persistent haematological toxicity including pancytopenia that does not resolve within 28 days following interruption, this medical product should be discontinued.
Due to the risk of thrombocytopenia, other medicinal products known to reduce platelet counts should be used with caution.
When starting the lower strength dose of the drug (two 50 mg/500 mg tablets) after dose interruption due to haematological adverse reactions, liver function should be monitored every two weeks for six weeks due to risk of increased abiraterone exposure, before resuming regular monitoring.
Hypertension
This medical product may cause hypertension and pre-existing hypertension should be adequately controlled before starting the drug treatment. Blood pressure should be monitored at least weekly for two months, monitored monthly afterwards for the first year and every other month thereafter during treatment with the drug.
Hypokalaemia, fluid retention, & cardiovascular adverse reactions due to mineralocorticoid excess
This medical product may cause hypokalaemia and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Co‑administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in incidence and severity of these adverse reactions. Caution is required in treating patients whose underlying medical conditions might be compromised by hypokalaemia (e.g., those on cardiac glycosides), or fluid retention (e.g., those with heart failure, severe or unstable angina pectoris, recent myocardial infarction or ventricular arrhythmia and those with severe renal impairment). QT prolongation has been observed in patients experiencing hypokalaemia in association with the drug treatment. Hypokalaemia and fluid retention should be corrected and controlled.
Before treating patients with a significant risk for congestive heart failure (e.g., a history of cardiac failure, or cardiac events such as ischaemic heart disease), cardiac failure should be treated and cardiac function optimised. Fluid retention (weight gain, peripheral oedema), and other signs and symptoms of congestive heart failure should be monitored every two weeks for three months, then monthly thereafter and abnormalities corrected. the drug should be used with caution in patients with a history of cardiovascular disease.
Management of cardiac risk factors (including hypertension, dyslipidaemia, and diabetes) should be optimised in patients receiving the drug and these patients should be monitored for signs and symptoms of cardiac disease.
Abiraterone acetate, a component of the drug, increases mineralocorticoid levels and carries a risk for cardiovascular events. Mineralocorticoid excess may cause hypertension, hypokalaemia, and fluid retention. Previous ADT exposure as well as advanced age are additional risks for cardiovascular morbidity and mortality. The AMPLITUDE and MAGNITUDE studies excluded patients with clinically significant heart disease as evidenced by myocardial infarction, arterial and venous thrombotic events in the past 6 months, severe or unstable angina, or NYHA Class II to IV heart failure or cardiac ejection fraction measurement of < 50%. Patients with a history of cardiac failure should be clinically optimised and appropriate management of symptoms instituted. If there is a clinically significant decrease in cardiac function, discontinuation of the drug should be considered.
Infections
In studies, severe infections including COVID-19 infections with fatal outcome occurred more frequently in patients treated with the drug.
Patients should be monitored for signs and symptoms of infection. Severe infections may occur in absence of neutropenia and/or leukopenia.
Pulmonary embolism (PE)
In studies, cases of PE were reported in patients treated with the drug with a higher frequency compared to control. Patients with a prior history of PE or venous thrombosis may be more at risk of a further occurrence. Patients should be monitored for clinical signs and symptoms of PE. If clinical features of PE occur, patients should be evaluated promptly, followed by appropriate treatment.
Posterior reversible encephalopathy syndrome (PRES)
PRES is a rare, reversible, neurological disorder which can present with rapidly evolving symptoms including seizures, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI).
There have been reports of PRES in patients receiving 300 mg niraparib (a component of the drug) as a monotherapy in the ovarian cancer population. In studies among prostate cancer patients treated with 200 mg of niraparib, there were no PRES cases reported.
In case of PRES, treatment with the drug should be permanently discontinued and appropriate medical management should be instituted.
Hepatotoxicity and hepatic impairment
Hepatotoxicity had been recognised as an important identified risk for abiraterone acetate, a component of the drug. The mechanism for hepatotoxicity of abiraterone acetate is not fully understood. Patients with moderate and severe hepatic impairment (NCI classification) and patients with Child‑Turcotte-Pugh Class B and C were excluded from the drug combination studies.
Marked increases in liver enzymes leading to treatment interruption or discontinuation occurred in clinical studies, although these were infrequent . Serum aminotransferase and total bilirubin levels should be measured prior to starting treatment, every two weeks for the first three months of treatment, and monthly thereafter for the first year and then every other month for the duration of treatment. When starting the lower strength dose of the drug (two 50 mg/500 mg tablets) after dose interruption, liver function should be monitored every two weeks for six weeks due to risk of increased abiraterone exposure , before resuming regular monitoring. If clinical symptoms or signs suggestive of hepatotoxicity develop, serum transaminases should be measured immediately. If at any time the ALT or AST rises above 5 times the ULN, treatment with the drug should be interrupted and liver function closely monitored. Re-treatment may take place only after return of liver function tests to the patient’s baseline and at a reduced dose level .
Treatment should be permanently discontinued in patients with elevations of ALT or AST > 20 Í ULN. Treatment should be permanently discontinued in patients who develop a concurrent elevation of ALT > 3 Í ULN and a total bilirubin > 2 Í ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation.
Moderate hepatic impairment (Child-Pugh Class B or any AST and TB > 1.5 x – 3 x ULN) has been shown to increase the systemic exposure to abiraterone and niraparib . There are no data on the clinical safety and efficacy of multiple doses of the drug when administered to patients with moderate or severe hepatic impairment. The use of the drug should be cautiously assessed in patients with moderate hepatic impairment, in whom the benefit clearly should outweigh the possible risk. the drug should not be used in patients with severe hepatic impairment .
Hypoglycaemia
Cases of hypoglycaemia have been reported when abiraterone acetate (a component of the drug) plus prednisone or prednisolone was administered to patients with pre-existing diabetes receiving pioglitazone or repaglinide (metabolised by CYP2C8) . Blood sugar should, therefore, be monitored in patients with diabetes.
Myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML)
MDS/AML, including cases with fatal outcome, have been reported in ovarian cancer studies among patients who received 300 mg of niraparib (a component of the drug).
For suspected MDS/AML or prolonged haematological toxicities that have not resolved with treatment interruption or dose reduction, the patient should be referred to a haematologist for further evaluation. If MDS/AML is confirmed, treatment with the drug should be permanently discontinued, and the patient should be treated appropriately.
Corticosteroid withdrawal and coverage of stress situations
Caution is advised and monitoring for adrenocortical insufficiency should occur if patients are withdrawn from prednisone or prednisolone. If the drug is continued after corticosteroids are withdrawn, patients should be monitored for symptoms of mineralocorticoid excess.
In patients on prednisone or prednisolone who are subjected to unusual stress, an increased dose of corticosteroids may be indicated before, during and after the stressful situation.
Bone density
Decreased bone density may occur in men with metastatic advanced prostate cancer. The use of abiraterone acetate in combination with a glucocorticoid could increase this effect.
Increased fractures and mortality in combination with Radium (Ra) 223 Dichloride
Treatment with this medical product plus prednisone or prednisolone in combination with Ra-223 treatment is contraindicated due to an increased risk of fractures and a trend for increased mortality among asymptomatic or mildly symptomatic prostate cancer patients as observed in clinical studies with abiraterone acetate.
It is recommended that subsequent treatment with Ra-223 not be initiated for at least five days after the last administration of the drug in combination with prednisone or prednisolone.
Skeletal muscle effects
Cases of myopathy and rhabdomyolysis have not been seen in patients treated with this medical product. In abiraterone acetate monotherapy studies, most cases developed within the first six months of treatment and recovered after abiraterone acetate withdrawal. Caution is recommended in patients concomitantly treated with medicinal products known to be associated with myopathy/rhabdomyolysis.
Interactions with other medicinal products
Strong inducers of CYP3A4 during treatment are to be avoided unless there is no therapeutic alternative, due to risk of decreased exposure of abiraterone.
See prescribing information for full details.

Very common: respiratory tract infections, urinary tract infection, anaemia, thrombocytopenia, neutropenia, leukopenia, lymphopenia, decreased appetite, hypokalaemia, hyperglycaemia, insomnia, dizziness, headache, hypertension, hot flush, dyspnoea, cough, constipation, nausea, vomiting, abdominal pain, diarrhoea, musculoskeletal pain, fatigue, oedema, weight decreased, blood creatinine increased.
Common: pneumonia, gastrointestinal infection, sepsis, lipid metabolism disorders, depression, anxiety, confusional state, lethargy, cognitive disorder, dysgeusia, cardiac failure, arrhythmia, angina pectoris, tachycardia, palpitations, pulmonary embolism, epistaxis, gastritis, abdominal distention, dyspepsia, stomatitis, dry mouth, hyperbilirubinaemia, rash, pruritus, photosensitivity reaction, haematuria, acute kidney injury, non-cardiac chest pain, blood alkaline phosphatase increased, AST increased, ALT increased, fractures.
See prescribing information for full details.

Pharmacokinetic interactions
No clinical study evaluating drug interactions has been performed using the drug. Interactions that have been identified in studies with individual components of the drug (niraparib or abiraterone acetate) determine the interactions that may occur with the drug.
Effects of other medicinal products on niraparib or abiraterone acetate
CYP3A4 inducers and inhibitors
Abiraterone is a CYP3A4 substrate. In a clinical study in healthy subjects pretreated with the strong CYP3A4 inducer rifampicin, 600 mg daily for six days, followed by a single dose of abiraterone acetate 1000 mg, the mean plasma AUC_∞ of abiraterone was decreased by 55%. Strong inducers of CYP3A4 (e.g., phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital, St. John’s wort [Hypericum perforatum]) during treatment with the drug should be avoided unless there is no therapeutic alternative .
In a separate clinical study in healthy subjects, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone.
Effects of niraparib or abiraterone acetate on other medicinal products
CYP2D6 substrates
Abiraterone is an inhibitor of CYP2D6. In a clinical study to determine the effects of abiraterone acetate plus prednisone (AAP) on a single dose of the CYP2D6 substrate dextromethorphan, the systemic exposure (AUC) of dextromethorphan was increased approximately 2.9-fold. The AUC₂₄ for dextrorphan, the active metabolite of dextromethorphan, increased approximately 33%. Dose reduction of medicinal products with a narrow therapeutic index that are metabolised by CYP2D6 should be considered. Examples of medicinal products metabolised by CYP2D6 include metoprolol, propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecainide, codeine, oxycodone and tramadol.
CYP2C8 substrates
Abiraterone is an inhibitor of CYP2C8. In a clinical study in healthy subjects, the AUC of pioglitazone, a CYP2C8 substrate, was increased by 46% and the AUCs for M-III and M-IV, the active metabolites of pioglitazone, each decreased by 10% when pioglitazone was given together with a single dose of 1000 mg abiraterone acetate. Patients should be monitored for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with the drug because of the abiraterone acetate component. Examples of medicinal products metabolised by CYP2C8 include pioglitazone and repaglinide .
Pharmacodynamic interactions
The data on niraparib, in combination with cytotoxic medicinal products, are limited. Caution should be taken if the drug is used in combination with live or live-attenuated vaccines, immunosuppressant agents or with other cytotoxic medicinal products.
Use with products known to prolong QT interval
Since androgen deprivation treatment may prolong the QT interval, caution is advised when administering the drug with medicinal products known to prolong the QT interval or medicinal products able to induce torsades de pointes, such as class IA (e.g., quinidine, disopyramide) or class III (e.g., amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc.
Use with spironolactone
Spironolactone binds to the androgen receptor and may increase prostate specific antigen (PSA) levels. Use with the drug is not recommended.

Women of childbearing potential/Contraception in males and females
It is not known whether components or their metabolites are present in semen.
During treatment and for four months after the last:
• A condom is required if the patient is engaged in sexual activity with a pregnant woman.
• If the patient is engaged in sex with a woman of childbearing potential, a condom is required along with another effective contraceptive method.
Pregnancy: This medical product is not for use in women.
There are no data from the use of the drug in pregnant women. the drug has the potential to cause foetal harm based on the mechanism of action of both components and findings from animal studies with abiraterone acetate.
Lactation: the drug is not for use in women.

There is no specific treatment in the event of the drug overdose. In the event of an overdose, physicians should follow general supportive measures and should treat patients symptomatically, including monitoring for arrhythmias, hypokalaemia and signs and symptoms of fluid retention. Liver function also should be assessed.